Because the brain is highly dependent on glucose, hypoglycemia is neurotoxic, and would be even more so except that hypoglycemia produces robust neuroprotective and counterregulatory responses. The mechanisms mediating these protective effects to hypoglycemia are unclear. However, DNA microarray data indicate that hypoglycemia induces adenosine, and adenosine receptors are known to mediate many neuroprotective responses to metabolic stresses such as ischemia and hypoxia. On the other hand, drugs that block the both the A1 and A2a adenosine receptors enhance counterregulatory responses in humans, including in diabetic patients. Since A1 adenosine receptors mediate cytoprotective responses to ischemia and hypoxia, A1 receptors may also mediate neuroprotective responses to hypoglycemia. In contrast, A2a receptors can actually potentiate neurotoxicity, possibly by antagonizing A1 receptors. Furthermore, A2a receptors mediate hypoglycemia-induced vasodilation, possibly accounting for the effects of caffeine and theophylline to enhance counterregulation. Therefore specific blockade of A2a receptors and/or activation of A1 receptors might improve neuroprotective and counterregulatory responses to hypoglycemia in patients with diabetes. To assess the feasibility of this approach, the proposed study will assess the influence of A1 and A2a receptors on responses to hypoglycemia, which has not been examined in vivo. Since pharmacological antagonists of the A1 and A2a receptors are of limited specificity and permeability through the blood-brain barrier, the proposed studies will assess responses to hypoglycemia in mice in which the A1 and/or A2a genes are genetically deleted (A1 and A2a knockout mice). These studies could lead to the development of A2a receptor antagonists to improve outcome of hypoglycemia in patients with diabetes.